The interferons are a family of glycoproteins whose secretion from cells is induced by a number of signals including viruses, double-stranded RNAs, other polynucleotides, antigens, and mitogens. Interferons exhibit multiple biological activities, including antiviral, antiproliferative, and immunomodulatory activities. At least three distinct types of human interferons, α, β, and γ, have been distinguished based on a number of factors, including anti-viral and anti-proliferative activities.
Interferon-β, (IFN-β) is the first identified effective treatment for those with multiple sclerosis (MS), and has been demonstrated to reduce the number of attacks suffered by patients with relapsing and remitting MS. IFN-β compositions are also useful in the treatment of hepatitis B and C infections.
As with all protein-based pharmaceuticals, one major obstacle that must be overcome in the use of IFN β as a therapeutic agent is the loss of pharmaceutical utility that can result from its instability in pharmaceutical formulations. Physical instabilities that threaten polypeptide activity and efficacy in pharmaceutical formulations include denaturation and formation of soluble and insoluble aggregates, while chemical instabilities include hydrolysis, imide formation, oxidation, racemization, and deamidation. Some of these changes are known to lead to the loss or reduction of the pharmaceutical activity of the protein of interest. In other cases, the precise effects of these changes are unknown, but the resulting degradative products are still considered to be pharmaceutically unacceptable due to the potential for undesirable side effects.
The instability of polypeptides in pharmaceutical preparations directly impacts their pharmaceutical utility, as the guidelines set for approval of protein-based pharmaceuticals emphasize that changes in the activity and the molecular characteristics of the polypeptide should be minimal. See, for example, the Nov. 30, 1995 report on stability testing of Biotechnological/Biological products issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (a tripartite organization which makes pharmaceutical-related policy recommendations for implementation in the European Union, Japan, and the USA), which states “[w]herever significant qualitative or quantitative changes indicative of degradation product formation are detected during long-term, accelerated, and/or stress stability studies, consideration should be given to potential hazards and to the need for characterization and quantification of degradation products within the long-term stability program.”
Consequently, there is a need for additional protein pharmaceutical compositions, including IFN-β compositions, comprising physiologically compatible stabilizers that are substantially free of reducing impurities, thereby stabilizing the protein and enhancing their pharmaceutical utility.